PROJECT SUMMARY/ABSTRACT Two decades of literature clearly document the wide scope of problems associated with post-traumatic stress disorder (PTSD)/alcohol and other drug use disorder (AOD) comorbidity. Evidence-based treatments, including present-focused trauma therapies, past-focused trauma therapies, and pharmacotherapies paired with trauma-focused (TF) or non-trauma focused (NTF) cognitive-behavioral therapies, are available for comorbid PTSD/AODs. However, the state of the science of PTSD/AOD treatment?based on single and multiple-site randomized controlled trials (RCTs), literature reviews, and meta-analyses?leaves the research community unable to make definitive practice and policy recommendations about (1) comparative effectiveness across PTSD/AOD treatments, (2) optimal treatments for different types of patients (e.g., men vs. women, civilians vs. veterans), and (3) and whether changes in PTSD, anxiety and depression mediate treatment effects on AODs differently depending on treatment type. The proposed study, which we call a virtual multisite clinical trial (VCT), will combine data from 50 PTSD/AOD treatment studies that we currently have in hand (total N = 4544), using three measurement and data analysis frameworks that have emerged across multiple independent disciplines: meta-analysis of individual patient data, integrative data analysis, and propensity score weighting specific to moderation and mediation analysis. Using these frameworks, we propose the following Aims: Aim 1: Develop scale scores of PTSD and AOD severity in the presence of study-level measurement non- invariance. Aim 2: Compare the efficacy of evidence-based treatment models for comorbid PTSD and AODs. Aim 3: Test for potential mediators of treatment effects on AODs across treatment models. Aim 4: Explore individual- and study-level moderators to inform for whom each of the treatment models works best. The project will yield the most definitive recommendations to date regarding optimal treatments for various types of patients across PTSD/AOD treatment settings. Our VCT approach will yield a synergy across PTSD/AOD treatment studies that will be greater than the sum of the constituent RCT parts, in a manner that would be cost- and effort-prohibitive for an analogous 50-site, multiple-treatment-arm RCT.